Salts of benzimidazole compound and use thereof

ABSTRACT

A sodium salt, magnesium salt, lithium salt, potassium salt, calcium salt or barium salt of (R)-2 -[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2 -pyridinyl]methyl]sulfinyl]-1H-benzimidazole, and a pharmaceutical composition comprising the salt. The novel salt is useful as an excellent antiulcer agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 11/811,801,filed Jun. 12, 2007, which is a Division of application Ser. No.10/343,142 filed Jan. 28, 2003, which is a U.S. National Stageapplication of PCT/JP01/06686, filed Aug. 3, 2001 which applications areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a salt of a benzimidazole compoundhaving an excellent pharmaceutical activity (e.g., an antiulcer action)and its application.

BACKGROUND ART

2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof having an antiulcer action is reported in JapanesePatent Application Laid-Open No. 50978/1986 (JP-61-50978A) and so on.

WO 94/27988 (Japanese Patent Application Laid-Open No. 509499/1995(JP-7-509499A)) discloses, as optically pure compounds, sodium,magnesium, lithium, potassium and calcium salts of(+)-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(omeprazole) which are optically pure.

WO 99/38513 discloses a method of treating ulcers, etc. which comprisesadministering an optically pure (R)-lansoprazole or a pharmaceuticallyacceptable salt thereof. However, this literature practically fails todisclose how to produce the salt.

WO 92/8716 discloses a pyridylmethylsulfiniyl-1H-benzimidazol compoundwhich is enantiomerically pure, or a salt thereof and a process forproducing the same.

WO96/2535 (U.S. Pat. No. 5,948,789, Japanese Patent ApplicationLaid-Open No. 504290/1998 (JP-10-504290A)) discloses a productionprocess which comprises subjecting a thio compound to an oxidationreaction for forming an optically active sulfoxide compound such asomeprazole and, if desired, converting the sulfoxide compound into asalt thereof by a conventional process.

The pyridylmethylsulfinyl-1H-benzimidazole compounds (e.g., omeprazole,lansoprazole) described in these literatures are relatively inferior instability. Moreover, it is difficult to provide an optically activelansoprazole with high purity. However, these literatures fail todisclose a process for improving a stability and a purity of anoptically active lansoprazole.

It is, therefore, an object of the present invention to provide anoptically active lansoprazole having a high stability and itsapplication (e.g., a pharmaceutical composition such as an antiulceragent).

Another object of the present invention is to provide an opticallyactive lansoprazole having a high-purity and its application.

Still another object of the present invention is to provide an opticallyactive lansoprazole which has an improved stability and is excellent insolubility and absorbability and its application.

DISCLOSURE OF INVENTION

The inventors of the present invention did intensive research, andfinally found that specific metal salts (especially, salts in the formof crystal) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolecan be synthesized for the first time and that such a salt unexpectedlyhas an excellent stability as a solid and an antiulcer action, andsatisfactorily serves as a pharmaceutical. The present invention wasaccomplished based on the above findings.

That is, the present invention relates to a sodium salt, a lithium salt,a potassium salt, a magnesium salt, a calcium salt, or a barium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.The salt may be a crystal. For example, the salt of the presentinvention may be a sodium salt (in particular a crystal) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,a potassium salt (in particular a crystal) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole,and the like. Further, the salt of the present invention may besolvated. In the salt in the form of crystal, the X-ray diffractionspectrum of the crystal may, for example, have the following diffractionpeaks:

(i) 15.02, 7.53, 7.05, 5.53, 4.17, 3.96, 3.42, 3.33 Å,

(ii) 16.00, 12.65, 7.98, 7.51, 6.35, 5.09, 4.99, 4.92, 4.82, 4.21 Å,

(iii) 8.89, 8.47, 5.64, 5.24, 4.84, 4.23, 4.20, 4.09, 3.60, 3.36 Å, or

(iv) 16.35, 8.17, 6.81, 5.78, 4.93, 4.50, 4.25, 4.08, 3.65, 3.36, 3.02Å.

According to the process of the present invention, a metal salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleis produced by reacting(R)-2-[[[3-methyl-4-2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolewith a compound of a metal selected from the group consisting of sodium,lithium, potassium, magnesium, calcium and barium. In the process, ametal salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolein a crystalline form can be obtained by subjecting the metal salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleto crystallization.

The present invention further discloses a pharmaceutical compositioncomprising the above-mentioned salt. The pharmaceutical composition isutilized as a prophylactic or therapeutic agent for digestive ulcer,gastritis, reflux esophagitis, NUD (Non-Ulcer Dyspepsia), gastriccancer, gastric MALT lymphoma, upper gastrointestinal hemorrhage, ulcercaused by a nonsteroidal anti-inflammatory agent, hyperacidity and ulcerdue to postoperative stress, or disease due to Helicobacter pylori.

The present invention furthermore discloses a method for preventing ortreating digestive ulcer, gastritis, reflux esophagitis, NUD (Non-UlcerDyspepsia), gastric cancer, gastric MALT lymphoma, uppergastrointestinal hemorrhage, ulcer caused by a nonsteroidalanti-inflammatory agent, hyperacidity and ulcer due to postoperativestress, or disease due to Helicobacter pylori, which comprisesadministering the above-mentioned salt to human being; and discloses useof the above-mentioned salt for manufacturing a pharmaceuticalcomposition.

Incidentally, in the specification, “sodium, lithium and potassium” andmetal compounds thereof are sometimes referred to as “alkali metals” and“alkali metal compounds”, respectively. Moreover, “magnesium, calcium,and barium” and metal compounds thereof are sometimes referred to as“alkaline earth metals” and “alkaline earth metal compounds”,respectively.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the X-ray powder diffraction analysis chart of the crystal ofExample 1.

FIG. 2 is the X-ray powder diffraction analysis chart of the crystal ofExample 2.

FIG. 3 is the X-ray powder diffraction analysis chart of the crystal ofExample 3.

FIG. 4 is the X-ray powder diffraction analysis chart of the crystal ofExample 6.

BEST MODE FOR CARRYING OUT THE INVENTION

The features of the present invention reside in that2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(hereinafter, sometimes referred to as simply “lansoprazole”) is anoptically active (R)-form, and that (R)-lansoprazole forms a salt with aspecific metal.

The sodium salt, magnesium salt, lithium salt, potassium salt, calciumsalt, or barium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleof the present invention (hereinafter, sometimes referred to simply as“the salt of the present invention”) is optically pure, and the opticalpurity of (R)-enantiomer is, for example, not less than 90% ofenantiomer excess (e.e.), preferably not less than 95% of enantiomerexcess, and more preferably not less than 99% of enantiomer excess.

The form of the salt of the present invention is not particularlylimited and may be an oil, a non-crystal, or a crystal. The preferredsalt form is a crystal. The crystal is identified by diffraction peaksof the X-ray diffraction spectrum. As the salt of a crystal form, theremay be mentioned a sodium salt, a potassium salt and the like.Concretely, as the salt of a crystal form, there may be mentioned

(i) crystal of a sodium salt of which the X-ray powder diffractionanalysis pattern has characteristic peaks at lattice spacings (d) of15.02, 7.53, 7.05, 5.53, 4.17, 3.96, 3.42, 3.33 Å,

(ii) crystal of a sodium salt solvated with isopropyl alcohol, of whichthe X-ray powder diffraction analysis pattern has characteristic peaksat lattice spacings (d) of 16.00, 12.65, 7.98, 7.51, 6.35, 5.09, 4.99,4.92, 4.82, 4.21 Å,

(iii) crystal of a monohydrate of a sodium salt of which the X-raypowder diffraction analysis pattern has characteristic peaks at latticespacings (d) of 8.89, 8.47, 5.64, 5.24, 4.84, 4.23, 4.20, 4.09, 3.60,3.36 Å,

(iv) crystal of a potassium salt of which the X-ray powder diffractionanalysis pattern has characteristic peaks at lattice spacings (d) of16.35, 8.17, 6.81, 5.78, 4.93, 4.50, 4.25, 4.08, 3.65, 3.36, 3.02 Å.

The salt of the present invention may be a solvate with a solvent(water, organic solvents), or may be a non-solvate. That is, the salt ofthe present invention may be a hydrate or not (or may be a non-hydrate).

The “hydrate” includes 0.5 hydrate to 5.0 hydrate. Among others, 0.5hydrate to 3.0 hydrate, for example, 0.5 hydrate, 1.0 hydrate, 1.5hydrate and 2.0 hydrate are preferred.

The salt of the present invention may contain a low-toxic or non-toxicsolvent, and may be solvated with a solvent as mentioned above. The“solvent” includes, for example, alcohols [e.g., C₁₋₄alkylalcohols suchas methanol, ethanol, 1-propanol and 2-propanol (isopropyl alcohol),benzyl alcohol]. Among them, ethanol and 2-propanol are preferred.

The content of the “solvent” is about 0.5 to 5.0 mol, preferably about0.5 to 2 mol (e.g., about 0.5 to 1.0 mol) and more preferably about 1.0mol relative to 1 mol of the salt of the present invention.

The salt of the present invention can be prepared by per se knownmethods, for example, the methods described in WO 94/27988 or analogousmethods thereto. For example, the salt of the present invention can beobtained by reacting(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolewith a compound of a metal selected from the group consisting of sodium,lithium, potassium, magnesium, calcium and barium. As the metalcompound, there may be mentioned, metal hydroxides, metal carbonates,metal hydrogencarbonates, metal alkoxides, metal amides and the like.The preferred metal compound includes metal hydroxides (e.g., sodiumhydroxide, potassium hydroxide, magnesium hydroxide), metal alkoxides(e.g., metal C₁₋₄alkoxides), and metal amides (e.g., sodium amide,potassium amide). These metal compounds can be used singly or incombination. More concretely, the salt of the present invention can beprepared by the following reactions 1 to 3.

(Reaction 1)

The sodium salt, magnesium salt, lithium salt, potassium salt, calciumsalt, or barium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleis obtained by reacting(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolewith a metal hydroxide (e.g., sodium hydroxide, magnesium hydroxide,lithium hydroxide, potassium hydroxide, calcium hydroxide, bariumhydroxide), a metal alkoxide (e.g., a metal C₁₋₄alkoxide such as sodiumethoxide, sodium methoxide, potassium ethoxide, potassium methoxide,magnesium ethoxide), or a metal amide (e.g., sodium amide, potassiumamide).

The amount of the “metal hydroxide, metal alkoxide, or metal amide” is0.1 mol to large excess mol, and preferably 0.5 to 2.0 mol (especially,0.8 to 1.5 mol) relative to 1 mol of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.The amount of the “metal hydroxide, metal alkoxide, or metal amide” isusually about 0.5 to 2 equivalents, preferably about 0.7 to 1.5equivalents, and more preferably about 0.8 to 1.2 equivalents relativeto 1 mol of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.

This reaction is usually carried out in the absence of a solvent, or inthe presence of an inert solvent. As the “inert solvent”, there may beused, for example, water, alcohols (e.g., methanol, ethanol, 1-propanol,2-propanol, butanol), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., acetonitrile, propionitrile), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide), ethers (e.g., diethylether, tert-butyl methyl ether, diisopropyl ether, dioxane,tetrahydrofuran), esters (e.g., ethyl formate, ethyl acetate),halogenated hydrocarbons (e.g., dichloromethane, chloroform,1,2-dichloroethane), hydrocarbons (e.g., n-hexane, cyclohexane, benzene,toluene), sulfoxides (e.g., dimethylsulfoxide), polar solvents (e.g.,sulfolane, hexamethylphosphoramide) and the mixed solvents of two kindsor more thereof. Among them, water and a mixed solvent of water and thealcohol (e.g., a mixed solvent of water and methanol, a mixed solvent ofwater and ethanol, or a mixed solvent of water and 2-propanol) arepreferred. The “inert solvent” is usually used in an amount of 1 to100-times by weight, and preferably about 2 to 50-times by weightrelative to(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.

The reaction temperature is usually about −10 to 80° C., preferablyabout 0 to 50° C., and more preferably about 0 to 30° C. The reactiontime is usually about 1 minute to 6 hours, preferably about 5 minutes to3 hours, and more preferably about 15 minutes to 1 hour.

Thus obtained salt can be separated and purified from a reaction mixtureby per se known separation means (e.g., concentration, concentrationunder a reduced pressure, solvent extraction, crystallization,recrystallization, redistribution, chromatography).

(Reaction 2)

The alkali metal salt (sodium, lithium or potassium salt) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleobtained by a method described above may be converted to an alkalineearth metal salt (magnesium, calcium, or barium salt) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleby reacting the alkali metal salt with an alkaline earth metal compound(a chloride or a sulfate such as magnesium chloride, magnesium sulfate,calcium chloride or barium chloride).

The amount of the alkaline earth metal compound “magnesium chloride,magnesium sulfate, calcium chloride, barium chloride and the like” is0.1 mol to large excess mol, and preferably 0.5 to 2.0 mol relative to 1mol of the alkali metal salt (sodium, lithium or potassium salt) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.The amount of the alkaline earth metal compound is usually about 0.5 to2 equivalents, preferably about 0.7 to 1.5 equivalents, and morepreferably about 0.8 to 1.2 equivalents relative to 1 mol of the alkalimetal salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.

This reaction is usually carried out in the presence of an inertsolvent. As the “inert solvent”, there may be used, for example, water,alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, butanol),ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g.,acetonitrile, propionitrile), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide), ethers (e.g., diethylether, tert-butyl methyl ether, diisopropyl ether, dioxane,tetrahydrofuran), sulfoxides (e.g., dimethylsulfoxide), polar solvents(e.g., sulfolane, hexamethylphosphoramide) and the mixed solvents of twokinds or more thereof. Among others, water, a mixed solvent of water andthe alcohol (e.g., a mixed solvent of water and ethanol, or a mixedsolvent of water and 2-propanol) are preferred.

The “inert solvent” is usually employed in an amount of 1 to 100-timesby weight, and preferably 2 to 50-times by weight relative to the alkalimetal salt (sodium, lithium or potassium salt) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.

The reaction temperature is usually −10 to 80° C., preferably 0 to 50°C. (e.g., 10 to 50° C.), and more preferably 15 to 30° C. The reactiontime is usually about 1 minute to 6 hours, preferably about 5 minutes to3 hours, and more preferably about 15 minutes to 1 hour.

The salt obtained in the foregoing manner can be separated and purifiedfrom a reaction mixture by per se known separation means (e.g.,concentration, concentration under a reduced pressure, solventextraction, crystallization, recrystallization, redistribution,chromatography).

(Reaction 3)

An alkaline earth metal salt (magnesium, calcium, or barium salt) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolecan be obtained by treating(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolewith an amine or ammonia, and reacting the treated product with analkaline earth metal compound (a chloride or a sulfate such as magnesiumchloride, magnesium sulfate, calcium chloride or barium chloride).

As the amine, there may be mentioned alkylamines (e.g.,monoC₁₋₆alkylamines such as ethylamine, propylamine, and isopropylamine,diC₁₋₆alkylamines such as diethylamine, dipropylamine anddiisopropylamine, triC₁₋₆alkylamines such as triethylamine,tripropylamine and diisopropylethylamine), cycloalkylamines (e.g.,C₃₋₈cycloalkylamines such as cyclohexylamine), arylamines (e.g.,aniline, N,N-dimethylaniline), aralkylamines (e.g., benzylamine),heterocyclic amines (e.g., pyridine, morpholine) and the like.

The amount of the “amine or ammonia” is 0.1 mol to large excess mol, andpreferably 0.5 to 2.0 mol (e.g., 0.7 to 1.5 mol) relative to 1 mol of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole.

This treatment reaction with amine or ammonia is usually carried out inthe presence of an inert solvent. As the “inert solvent”, there may beused, for example, water, alcohols (e.g., methanol, ethanol, 1-propanol,2-propanol, butanol), ketones (e.g., acetone, methyl ethyl ketone),nitriles (e.g., acetonitrile, propionitrile), amides (e.g., formamide,N,N-dimethylformamide, N,N-dimethylacetamide), ethers (e.g., diethylether, tert-butyl methyl ether, diisopropyl ether, dioxane,tetrahydrofuran), sulfoxides (e.g., dimethylsulfoxide), polar solvents(e.g., sulfolane, hexamethylphosphoramide) and the mixed solvents of twokinds or more thereof.

The reaction temperature is usually −10 to 80° C., preferably 0 to 50°C., and more preferably 0 to 30° C. The reaction time is usually about 1minute to 6 hours, preferably about 5 minutes to 3 hours, morepreferably about 15 minutes to 1 hour.

After the treatment with amine or ammonia, the reaction with an alkalineearth metal compound (e.g., magnesium chloride, magnesium sulfate,calcium chloride or barium chloride) may be carried out in the similarmanner to the above (reaction 2).

The salt obtained by the above-mentioned way can be separated andpurified by per se known separation means (e.g., concentration,concentration under a reduced pressure, solvent extraction,crystallization, recrystallization, redistribution, chromatography) fromthe reaction mixture.

(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolecan be prepared, for example, by subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleor a salt thereof to an optical resolution or by subjecting2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazoleto an asymmetric oxidation. Incidentally, the racemic body can beprepared by known methods, for example, methods described in EP 174726(Japanese Patent Application Laid-Open No. 50978/1986 (JP-61-50978A))and EP 302720, or analogous methods thereto.

Methods of optical resolution includes per se known methods, forexample, a fractional recrystallization method, a chiral column method,a diastereomer method, and a method with the use of a microorganism oran enzyme and so forth. Asymmetric oxidation may include per se knownmethods.

The “fractional recrystallization method” includes a method in which asalt of a racemate with an optically active compound [e.g., (+)-mandelicacid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid,(+)-1-phenethylamine, 1-(1-naphthyl)ethylamine,1-(2-naphthyl)ethylamine, (−)-1-phenethylamine, cinchonine, quinidine,(−)-cinchonidine, brucine, etc.] is formed, the salt is separated byfractional recrystallization etc., and, if desired, subjected to aneutralization step, to give a free optical isomer.

The “chiral column method” includes a method in which a racemate or asalt thereof is applied to a column for an optical isomer separation(chiral column). In the case of liquid chromatography, for example,optical isomers are separated by adding a racemate to a chiral columnsuch as ENANTIO-OVM (produced by Tosoh Corporation) or CHIRAL series(produced by Daicel Chemical Industries, Ltd.), and developing theracemate in water, a buffer (e.g., phosphate buffer), an organic solvent(e.g., hexane, ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine, triethylamine, etc.), or a solventmixture thereof. In the case of gas chromatography, for example, achiral column such as CP-Chirasil-DeX CB (produced by GL Science Inc.)is used for separating optical isomers.

The “diastereomer method” includes a method in which a racemate and anoptically active reagent are reacted (preferably, an optically activereagent is reacted to the 1-position of the benzimidazole group) to givea diastereomer mixture, then the mixture is subjected to an conventionalseparation mean (e.g., fractional recrystallization, chromatography,etc.) to form one diastereomer, and the diastereomer is subjected to achemical reaction (e.g., acid hydrolysis reaction, basic hydrolysisreaction, hydrogenolysis reaction, etc.) to separate the opticallyactive reagent moiety from the reaction product, thereby the desiredoptical isomer is obtained. The “optically active reagent” includes, forexample, optically active organic acids such as MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid] and (−)-menthoxyaceticacid; and optically active alkoxymethyl halides such as(1R-endo)-2-(chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane, etc.

By subjecting thus obtained salt to a crystallization, the metal salt of(R)-lansoprazole in the form of crystal can be obtained. Thecrystallization method includes per se known methods, for example, acrystallization from a solution, a crystallization from a vapor, and acrystallization from a molten form.

Methods of the “crystallization from a solution” include, for example, aconcentration method, a slow cooling method, a reaction method(diffusion method, electrolysis method), a hydrothermal growth method, afusing agent method, and so forth. Solvents to be used include, forexample, aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.),saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.),ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, etc.), nitriles (e.g., acetonitrile, etc.), ketones (e.g.,acetone, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.), acid amides(e.g., N,N-dimethylformamide, N,N-dimethylacetoamide, etc.), esters(e.g., methyl acetate, ethyl acetate, etc.), alcohols (e.g., methanol,ethanol, isopropyl alcohol, butanol, etc.), water, and so forth. Thesesolvents may be used singly or as a mixture of two or more kinds inappropriate ratios (e.g., 1:1 to 1:100 (volume ratio)).

Methods of the “crystallization from a vapor” include, for example, agasification method (sealed tube method, gas stream method), a gas phasereaction method, a chemical transportation method, and so forth.

Methods of the “crystallization from a molten form” include, forexample, a normal freezing method (pulling-up method, temperaturegradient method, Bridgman method), a zone melting method (zone levelingmethod, float zone method), a special growth method (VLS method, liquidphase epitaxis method), and so forth.

Incidentally, the crystallization of the salt of (R)-lansoprazole isusually carried out through the use of (1) crystallization due tocooling a solvent solution (organic solvent solution such as an alcohol,an ether and a hydrocarbon) heated to about 50 to 120° C. (preferablyabout 70 to 100° C.) in which (R)-lansoprazole is dissolved, or (2)crystallization due to addition of a poor solvent into the solventsolution (in particular, concentrated liquid). According to such acrystallization method, a solvated crystal can be also obtained, and anabsolute crystal can be also obtained by heat-treating a mixturesolution containing (R)-lansoprazole and a solvent to a high temperature(e.g., a reflux temperature of the solvent) and cooling.

For analyzing the resultant crystal, X-ray diffraction crystallographicanalysis is commonly used. In addition, crystal orientation can also bedetermined by a mechanical method, an optical method, etc.

The salt of the present invention is useful as a pharmaceutical becauseof excellent antiulcer action of the salt, gastric acidsecretion-inhibiting action, mucosa-protecting action, anti-Helicobacterpylori action, etc., and low toxicity of the salt. Furthermore, the salthas a high purity and an excellent stability, and can be stored at aroom temperature for a long period of time, in addition ensures simplehandling thereof, as a result, a solid pharmaceutical composition can beproduced from the salt with advantageous reproducibility. In addition,when orally administered, the salt of the present invention is excellentin solubility and absorbability and more rapidly expresses an action oreffect thereof. Moreover, when the salt of the present invention isadministered, a C_(max) (maximum blood concentration) and an AUC (areaunder the concentration-time curve) are increased, and the salt tends tobe metabolized with difficulty because of an increased protein-bindingrate, prolonging a duration of action or effectiveness. The salt of thepresent invention is therefore useful as a pharmaceutical of low dosesand low prevalence of adverse reactions. In particular, the crystal ofthe salt of the present invention is highly pure and has an improvedstability (see Experimental Example 1). Further, the crystal of the saltof the present invention ensures an increased protein-binding rate and aprolonged length of effectiveness, in addition, is advantageous tohandling and operatability in a preparation of a pharmaceutical.

Incidentally, with respect to the crystal, not all compounds and saltsinclusive of the salt of the present invention can be crystallized, butthe salt of the present invention has been obtained in the form of acrystal for the first time, and the inventors of the present inventionfound that the salt and the crystal thereof have excellent properties asa pharmaceutical, as described above.

The salt of the present invention is also useful in mammals (e.g., humanbeings, nonhumans such as monkeys, sheep, bovines, horses, dogs, cats,rabbits, rats, mice, etc.) for the treatment and prophylaxis (orprevention) of digestive ulcer (peptic ulcer) (e.g., gastric ulcer,duodenal ulcer, stomal ulcer, Zollinger-Ellison syndrome, etc.),gastritis, reflux esophagitis, NUD (Non-Ulcer Dyspepsia), gastric cancer(inclusive of gastric ulcer accompanied with an enhanced production ofinterleukin-1(3 due to genetic polymorphism of interleukin-1), gastricMALT lymphoma; disease due to Helicobacter pylori; uppergastrointestinal hemorrhage due to digestive ulcer, acute stress ulcerand hemorrhagic gastritis; upper gastrointestinal hemorrhage due toinvasive stress (stress from major surgery necessitating intensivemanagement after surgery, and from cerebral vascular disorder, headtrauma, multiple organ failure and extensive burn necessitatingintensive treatment); and ulcer caused by a nonsteroidalanti-inflammatory agent. Further, the salt of the present invention isalso useful for Helicobacter pylori eradication; suppression of theabove upper gastrointestinal hemorrhage; treatment and prophylaxis ofhyperacidity and ulcer due to postoperative stress; pre-anestheticadministration etc.

The salt of the present invention is of low toxicity and can be safelyadministered orally or non-orally (e.g., topical, rectal and intravenousadministration, etc.), as such or in the form of pharmaceuticalcompositions formulated with a pharmacologically acceptable carrier,e.g., solids (tablets (including sugar-coated tablets and film-coatedtablets), powders, granules, capsules (including soft capsules), orallydisintegrating tablets, suppositories), liquids (including injectablepreparations), ointments, cataplasms or the like in accordance with acommonly known method. The pharmaceutical composition can be alsoadministrated as sustained-release preparations or targets (targetagents) by utilizing a drug delivery system. That is, the salt of thepresent invention is advantageously used for producing a pharmaceuticalcomposition for prophylaxis and treatment of the above disease,Helicobacter pylori eradication, suppression of the above uppergastrointestinal hemorrhage, pre-anesthetic administration etc.

The content of the salt of the present invention in the pharmaceuticalcomposition of the present invention is about 0.01 to 100% by weightrelative to the entire or whole composition. Varying depending on asubject of administration, a route of administration, a target diseaseetc., the dose of the salt as an active ingredient is about 0.5 to 1,500mg/day, and preferably about 5 to 150 mg/day, for example, when the saltis orally administered as an antiulcer agent to an adult human (60 kg).The salt of the present invention may be administered once daily or in 2to 3 divided doses per day.

Pharmacologically acceptable carriers that may be used for producing thepharmaceutical composition of the present invention include variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, dissolution aids, suspending agents, isotonizing agents,buffers and soothing agents or pain-relieving agents for liquidpreparations. Other ordinary pharmaceutical additives such aspreservatives, antioxidants, coloring agents, sweetening agents, souringagents, bubbling agents and flavorings may also be used if necessary.

The “excipients” include, for example, lactose, sucrose, D-mannitol, astarch, a cornstarch, a crystalline cellulose, a light silicic anhydrideand titanium oxide.

The “lubricants” include, for example, magnesium stearate, a sucrosefatty acid ester, a polyethylene glycol, talc and stearic acid.

The “binders” include, for example, cellulose derivatives (ahydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethylcellulose, a low-substituted hydroxypropyl cellulose, an ethylcellulose, a carboxymethyl cellulose sodium, a crystalline celluloseetc.), a starch, a polyvinylpyrrolidone, a polyvinylalcohol, a gumarabic powder, a gelatin, a pullulan and the like.

The “disintegrants” include (1) a crosslinked povidone, (2) what iscalled super-disintegrants such as crosslinked carmellose sodium(FMC-Asahi Chemical) and carmellose calcium (Gotoku Chemical CompanyLtd.), (3) a carboxymethyl starch sodium (e.g., product of MatsutaniChemical Industry Co., Ltd.), (4) a low-substituted hydroxypropylcellulose (e.g., product of Shin-Etsu Chemical Co., Ltd.), (5) acornstarch, and so forth. The “crosslinked povidone” may be anycrosslinked polymer having the chemical name 1-ethenyl-2-pyrrolidinonehomopolymer, including a polyvinylpyrrolidone (PVPP) and a1-vinyl-2-pyrrolidinonehomopolymer, and is exemplified by Colidon CL(produced by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10(produced by ISP) and Polyplasdon INF-10 (produced by ISP).

The “water-soluble polymers” include, for example, ethanol-soluble andwater-soluble polymers [e.g., cellulose derivatives such as ahydroxypropyl cellulose (hereinafter also referred to as HPC), apolyvinylpyrrolidone] and ethanol-insoluble and water-soluble polymers[e.g., cellulose derivatives such as a hydroxypropylmethyl cellulose(hereinafter also referred to as HPMC), a methyl cellulose and acarboxymethyl cellulose sodium, a sodium polyacrylate, a polyvinylalcohol, a sodium alginate, a guar gum].

The “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. The basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogencarbonate,disodium hydrogenphosphate, etc. The basic inorganic salts of potassiuminclude, for example, potassium carbonate, potassium hydrogencarbonate,etc. The basic inorganic salts of magnesium include, for example, heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, magnesium metasilicate aluminate, magnesium silicate,magnesium aluminate, synthesized hydrotalcite [Mg₆Al₂(OH)₁₆.CO₃.4H₂O],alumina hydroxide magnesium, and so forth. Among others, preferred isheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide, etc. The basic inorganic salts of calcium include,for example, precipitated calcium carbonate, calcium hydroxide, etc.

The “solvents” include, for example, water for injection, alcohols(e.g., ethanol), ethylene glycol, propylene glycol, macrogol, fats andoils (e.g., a sesame oil, a corn oil and an olive oil).

The “dissolution aids” include, for example, a polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate andsodium citrate.

The “suspending agents” include, for example, surfactants (anionic,cationic, nonionic, or amphoteric surfactants) such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride and monostearicglycerol, a polyoxyethylene glycerin fatty acid ester, a sorbitane fattyacid ester, a polyoxyethylenesorbitane fatty acid ester, apolyoxyethylene-polyoxypropylene block copolymer; and hydrophilicpolymers such as a polyvinyl alcohol, a polyvinylpyrrolidone, acarboxymethyl cellulose sodium, a methyl cellulose, a hydroxymethylcellulose, a hydroxyethyl cellulose and a hydroxypropyl cellulose.

The “isotonizing agents” include, for example, glucose, D-sorbitol,D-mannitol, sodium chloride, glycerol and the like.

The “buffers” include, for example, buffer solutions of phosphates,acetates, carbonates, citrates, borates or the like.

The “soothing agents” include, for example, benzyl alcohol and the like.

The “preservatives” include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid or salts thereof.

The “antioxidants” include, for example, sulfites, ascorbic acid andα-tocopherol.

The “coloring agents” include, for example, food colors such as FoodColor Yellow No. 5, Food Color Red No. 2 and Food Color Blue No. 2; andfood lake colors, colcothar and the like.

The “sweetening agents” include, for example, sugars, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

The “souring agents” include, for example, citric acid (citricanhydride), tartaric acid and malic acid.

The “bubbling agents” include, for example, sodium bicarbonate.

The “flavorings” may be synthetic substances or naturally occurringsubstances, and include, for example, lemon, lime, orange, menthol andstrawberry.

The salt of the present invention may be prepared as a preparation foran oral administration in accordance with per se known methods, forexample, by compression-shaping or molding a mixture containing thesalt, an excipient, a disintegrant, a binder, a lubricant, or the like,and subsequently coating the resultant product if necessary by per seknown methods for the purpose of taste masking, enteric dissolution orsustained release. For an enteric preparation, an intermediate layer maybe provided by a commonly known method between the enteric layer and thedrug-containing layer for the purpose of separation of the two layers.

For preparing the salt of the present invention as an orallydisintegrating tablet, for example, the following method is available,wherein;

a core containing a crystalline cellulose and lactose is coated with thesalt of the present invention and, if necessary, a basic inorganic salt,and is further coated with a coating layer containing a water-solublepolymer to form a composition,

the composition is coated with an enteric coating layer containing apolyethylene glycol, further coated with an enteric coating layercontaining triethyl citrate, still further coated with an entericcoating layer containing a polyethylene glycol, and still yet furthercoated with mannitol to form fine granules, and

the fine granules are mixed with additives to be shaped or molded. Theabove-mentioned “enteric coating layer” includes, for example, aqueousenteric polymer substrates such as a cellulose acetate phthalate (CAP),a hydroxypropylmethyl cellulose phthalate, a hydroxymethyl celluloseacetate succinate, (meth)acrylic acid copolymers [e.g., Eudragit L30D-55(trade name; produced by Rohm), Colicoat MAE30DP (trade name; producedby BASF), Polykid PA30 (trade name; produced by San-yo Chemical)], acarboxymethylethyl cellulose and a shellac; sustained-release substratessuch as (meth)acrylic acid copolymers [e.g., Eudragit NE30D (tradename), Eudragit RL30D (trade name). Eudragit RS30D (trade name), etc.];water-soluble polymers; plasticizers such as triethyl citrate, apolyethylene glycol, an acetylated monoglyceride, a triacetine and acastor oil; and mixtures thereof. The above-mentioned “additive”includes, for example, water-soluble sugar alcohols (e.g., sorbitol.mannitol, multitol, reduced starch saccharides, xylitol, reducedparatinose, erythritol, etc.), crystalline celluloses [e.g., Ceolas KG801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, AvicelRC-591 (a crystalline cellulose carmellose sodium)], and low-substitutedhydroxypropyl celluloses [e.g., LH-22, LH-32, LH-23; LH-33 (Shin-EtsuChemical Co., Ltd.) and mixtures thereof]; and binders, souring agents,bubbling agents, sweetening agents, flavorings, lubricants, coloringagents, stabilizers, excipients, disintegrants etc. are also used.

The salt of the present invention may be used in combination with otheringredients (e.g., 1 to 3 other active ingredients).

The “other active ingredients” include, for example, substances havingan anti-Helicobacter pylori action, imidazole-series compounds, bismuthsalts, quinolone-series compounds, and so forth. Of these substances,preferred are substances having an anti-Helicobacter pylori action,imidazole-series compounds etc. The “substances having ananti-Helicobacter pylori action” include, for example, antibioticpenicillins (e.g., amoxicillin, benzylpenicillin, piperacillin,mecillinam, etc.), antibiotic cefems (e.g., cefixime, cefaclor, etc.),antibiotic macrolides (e.g., antibiotic erythromycins such aserythromycin, clarithromycin etc.), antibiotic tetracyclines (e.g.,tetracycline, minocycline, streptomycin, etc.), antibioticaminoglycosides (e.g., gentamicin, amikacin, etc.), imipenem, and soforth. Of these substances, preferred are antibiotic penicillins,antibiotic macrolides etc. The “imidazole-series compounds” include, forexample, metronidazole, miconazole, etc. The “bismuth salts” include,for example, bismuth acetate, bismuth citrate, etc. The“quinolone-series compounds” include, for example, ofloxacin,ciploxacin, etc. In particular, it is preferred for Helicobacter pylorieradication that the salt of the present invention is used incombination with antibiotic penicillins (e.g., amoxicillin) and/orantibiotic erythromycins (e.g., clarithromycin).

The “other active ingredients” and the salt of the present invention mayalso be used in combination as a mixture prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injectable preparations,suppositories, sustained-release preparations, etc.], in accordance withper se known methods, and may also be prepared as separate preparationsand administered to the same subject simultaneously or at a timeinterval.

Industrial Applicability

The salt of the present invention is useful as a pharmaceutical becausethe salt is excellent in an antiulcer action, a gastric acidsecretion-inhibiting action, a mucosa-protecting action, ananti-Helicobacter pylori action etc., and because the salt is of lowtoxicity. Furthermore, the salt has a high purity and an excellentstability, and ensures a storage thereof at a room temperature for along period of time, in addition simplifies a handling thereof, as aresult, the salt ensures a production of a solid pharmaceuticalcomposition with advantageous reproducibility. In addition, when orallyadministered, the salt of the present invention is excellent insolubility and absorbability, and an action or effect thereof is rapidlyexpressed. Moreover, when the salt of the present invention isadministered, a Cmax (maximum blood concentration) and an AUC (areaunder the concentration-time curve) are increased, and the salt tends tobe metabolized with difficulty because of an increased protein-bindingrate, prolonging a duration of action or effectiveness. The salt of thepresent invention is therefore useful as a pharmaceutical of low dosesand low prevalence of adverse reactions. In particular, the crystal ofthe salt of the present invention ensures a high purity, an improvedstability, and an increased protein-binding rate and a prolonged lengthof effectiveness, in addition, is advantageous to handling andoperatability in a preparation of a pharmaceutical.

EXAMPLES

The following reference example and examples are intended to describethis invention in further detail and should by no means be interpretedas defining the scope of the invention.

In the following reference example and examples, the term “a roomtemperature” indicates about 15 to 30° C.

¹H-NMR spectra were determined with CDCl₃ or DMSO-d₆ as the solventusing a Varian Gemini-200; data are shown in chemical shift δ (ppm) fromthe internal standard tetramethylsilane.

IR was determined using a SHIMADZU FTIR-8200.

Optical rotation [α]_(D) was determined at 20° C. using a DIP-370Digital polarimeter (produced by JASCO).

X-ray powder diffraction was determined using a X-ray Powder Diffractionmeter Rigaku RINT2500 (ultraXl8) No. PX-3.

Optical purity (% ee) was determined by high performance liquidchromatography with use of a chiral column in accordance with thefollowing conditions.

Conditions of high performance liquid chromatography;

column: CHIRALCEL OD (manufactured by Daicel Chemical Industries, Ltd.)

mobile phase: hexane/ethanol=90/10

flow rate: 1.0 ml/min

detection wavelength: UV 285 nm

The other symbols used herein have the following definitions:

-   -   s: singlet    -   d: doublet    -   t: triplet    -   q: quartet    -   m: multiplet    -   bs: broad singlet    -   J: a coupling constant

Reference Example 1(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole

In a stream of nitrogen,2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole(4.5 kg, 12.7 mol, water content of 1.89 g), toluene (22 L), water (25g, 1.39 mol, total water content of 1.49 mol) and (+)-diethyl tartrate(0.958 L, 5.60 mol) were mixed. In a stream of nitrogen, to the mixturewas added titanium(IV) isopropoxide (0.747 L, 2.53 mol) at 50 to 60° C.,and stirred for 30 minutes at the same temperature. In a stream ofnitrogen, to the resulting mixture liquid was addeddiisopropylethylamine (0.733 L, 4.44 mol) at a room temperature, furtheradded cumenehydroperoxide (6.88 L, content of 82%, 37.5 mol) at −5 to 5°C., and stirred at −5 to 5° C. for 1.5 hours to obtain a liquid reactionmixture. In a stream of nitrogen, to the reaction liquid was added 30%sodium thiosulfate aqueous solution (17 L) to decompose residualcumenehydroperoxide. The reaction liquid was phase-separated, and water(4.5 L), heptane (13.5 L), t-butyl methyl ether (18 L) and heptane (27L) were successively added to the resulting organic phase, and themixture was subjected to crystallization under stirring. The resultingcrystal was separated and washed with t-butyl methyl ether-toluene(t-butyl methyl ether:toluene=4:1)(4 L). Under stirring, an acetone (20L) suspension of the wet crystal was added dropwise to a liquid mixtureof acetone (7 L) and water (34 L), and then added water (47 L) thereto.The precipitated crystal was separated and washed with acetone-water(acetone:water=1:3) (4 L) and with water (12 L). The wet crystal wasdissolved in ethyl acetate (45 L) and water (3 L) to be phase-separated.A slight amount of insoluble matter (undissolved material) in an organicphase was filtrated off, and then triethylamine (0.2 L) was added to theorganic phase and concentrated under a reduced pressure until the liquidvolume of the organic phase was to about 7 L. To the resultantcondensate were added methanol (2.3 L), about 12.5% aqueous ammonia (23L) at about 50° C. and t-butyl methyl ether (22 L) at about 50° C. to bephase-separated. To the resultant organic phase was added about 12.5%aqueous ammonia (11 L) to be phase-separated (the operation was repeatedonce). The aqueous phases were combined with each other, ethyl acetate(22 L) was added thereto, and under cooling, acetic acid was addeddropwise thereto for adjusting pH to about 8. The resulting liquid wasphase-separated and the resultant aqueous phase was extracted with ethylacetate (11 L). The organic phases were combined with each other, andwashed with about 20% brine (11 L). After adding triethylamine (0.2 L),the organic phase was concentrated under a reduced pressure. To theconcentrate was added acetone (5 L) and concentrated under a reducedpressure. The resulting concentrate was dissolved in acetone (9 L), theresulting mixture was added dropwise to a mixture liquid of acetone (4.5L) and water (22.5 L), and then water (18 L) was added dropwise thereto.The precipitated crystal was separated, and was washed with coldacetone-water (acetone:water=1:3) (3 L) and water (12 L), successively.The wet crystal was dissolved in ethyl acetate (32 L). The separatedaqueous phase was separated by separation operation, and the resultingorganic phase was concentrated under a reduced pressure until the liquidvolume became to be about 14 L. To the residue were added ethyl acetate(36 L) and active carbon (270 g), and after stirring, active carbon wasfiltered off. The resultant filtrate was concentrated under a reducedpressure until the liquid volume was to about 14 L. To the concentratewas added dropwise heptane (90 L) at about 40° C. After stirring at thesame temperature for about 30 minutes, the resultant crystal wasseparated, and washed with ethyl acetate-heptane (ethylacetate:heptane=1:8, 6 L) at about 40° C. After drying, the titlecompound (3.4 kg) was obtained. The enantiomer excess rate of thecompound was 100% ee.

Example 1

The crystal of sodium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole

To ethanol solution (50 mL) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(5.00 g) was added 1N sodium hydroxide aqueous solution (13.5 mL) undercooling with an ice. After filtration, the filtrate was concentratedunder a reduced pressure. The residue was dissolved by adding ethanol(50 mL), and the resultant solution was concentrated under a reducedpressure. The residue was repeatedly dissolved by adding ethanol (50 mL)and the resultant solution was concentrated under a reduced pressure. Tothe resulting foamy material was added diethyl ether (50 mL), and thenthe resultant mixture was subjected to an ultrasonic treatment, and washeated with refluxing for 30 minutes. After cooling the mixture to aroom temperature, the precipitated solid was filtrated off and theresultant solid was washed with diethyl ether (10 mL). The solid wassuspended in diethyl ether (50 mL), and the suspension was heated withrefluxing for 30 minutes. After cooling the suspension to a roomtemperature, the precipitated solid was filtrated, and washed withdiethyl ether (10 mL). The solid was suspended in diethyl ether (50 mL)again and the suspension was heated with refluxing for 1 hour. Aftercooling the resulting suspension to a room temperature, the precipitatedsolid was filtered, washed with diethyl ether (10 mL) and dried under areduced pressure at 60° C. to obtain 3.70 g of white powder.

The resulting white powder (0.50 g) was suspended in a mixture solutionof ethanol (0.5 mL) and toluene (50 mL), and was the suspension heatedwith refluxing for 16 hours with use of a reactor equipped with a tubefor dehydration charged with molecular sieve. After cooling theresulting mixture to a room temperature, the precipitated solid wasfiltrated and washed twice with toluene (5 mL). After drying at 60° C.under a reduced pressure, the title compound (0.48 g) was obtained. Thedata of X-ray powder diffraction is shown in Table 1, and the chart ofX-ray powder diffraction is shown in FIG. 1.

Elemental Analysis

Calculated (as C₁₆H₁₃N₃O₂SF₃Na):

C: 49.11; H, 3.35, N, 10.74, S: 8.19, F: 14.56.

Found: C: 48.80; H, 3.51, N, 10.62, S: 8.34, F: 14.29

Na content by atomic absorption spectrometry: 6.0% (Calculated: 5.87%).

¹H-NMR (DMSO-d₆): 2.21 (3H,$), 4.46 (1H, d, J=13.0 Hz), 4.78 (1H, d,J=13.0 Hz), 4.90 (2H, q, J=8.8 Hz), 6.89-6.94 (2H, m), 7.08 (1H, d,J=5.8 Hz), 7.45-7.51 (2H, m), 8.36 (1H, d, J=5.8 Hz)

IR (νcm⁻¹): 3400, 1584, 1474, 1454, 1377, 1312, 1265, 1167, 1113

[α]_(D)=+107.9° (c=0.999%, MeOH)

TABLE 1 relative half-value d-value intensity 2θ (°) width [Å] [%] 5.8800.118 15.0181 100 11.740 0.165 7.5317 30 12.540 0.165 7.0530 19 16.0000.141 5.5347 10 21.280 0.141 4.1719 11 22.440 0.188 3.9588 14 26.0200.188 3.4216 11 26.760 0.165 3.3287 10

Example 2

The crystal solvated with isopropyl alcohol of sodium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole

To(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole(150.0 g, 0.41 mol) was added methanol (225 mL) to dissolve, and 20%sodium hydroxide aqueous solution (81 g, 0.41 mol) was added thereto.The mixture was concentrated under a reduced pressure. To the residuewas added isopropyl alcohol (1,500 mL) to dissolve, and the resultantmixture was stirred at a room temperature for about 24 hours. Theprecipitated crystal was separated and washed with isopropyl alcohol(300 mL). After drying at 40° C. under a reduced pressure, the titlecrystal (142.0 g) was obtained. The data of X-ray powder diffraction isshown in Table 2, and the chart of X-ray powder diffraction is shown inFIG. 2.

Elemental Analysis

Calculated (as C₁₆H₁₃N₃O₂SF₃Na.C₃H₈O.1.5H₂O):

C: 47.70; H 5.06; N, 8.78; S: 6.70; F: 11.91.

Found: C: 47.68; H, 5.02; N, 8.70; S: 7.00; F: 11.84 Na content byatomic absorption spectrometry: 4.8%. (Calculated: 4.80%)

TABLE 2 relative half-value d-value intensity 2θ (°) width [Å] [%] 5.5200.141 15.9967 98 6.980 0.165 12.6536 100 11.080 0.165 7.9788 54 11.7800.165 7.5062 32 13.940 0.235 6.3476 36 17.400 0.188 5.0924 29 17.7600.235 4.9900 43 18.020 0.141 4.9186 48 18.380 0.188 4.8230 42 21.1000.212 4.2070 30

Example 3

The crystal of sodium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazolemonohydrate

To(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole(50.0 g, 0.14 mol) was added sodium hydroxide (5.4 g, 0.14 mol), water(100 mL) and methanol (120 mL) to dissolve, and the mixture wasconcentrated under a reduced pressure. To the residue was added water(20 mL) to crystallize, and the resultant was stirred for about 1 hourunder cooling with an ice. The precipitated crystal was separated andwashed with water (100 mL). The crystal was dried at 40° C. under areduced pressure. To the dried crystal were added isopropyl alcohol(158.3 mL) and water (31.7° mL), the mixture was stirred andconcentrated until the liquid volume was reduced to about 100 mL.Isopropyl alcohol (100 mL) was added thereto to crystallize, and theresultant was stirred at a room temperature for about 1 hour. Theprecipitated crystal was separated and washed with isopropyl alcohol(100 mL). The crystal was dried at 40° C. under a reduced pressure. Tothe dried crystal was added water (340 mL) and the mixture was stirredat a room temperature for about 3 hours. The precipitated crystal wasseparated and washed with water (100 mL). After drying at 40° C. under areduced pressure, the title crystal (20.0 g) was obtained. The data ofX-ray powder diffraction is shown in Table 3, and the chart of X-raypowder diffraction is shown in FIG. 3.

Elemental Analysis

Calculated (as C₁₆H₁₃N₃O₂SF₃Na.H₂O):

C: 46.94; H 3.69; N, 10.26; S: 7.83; F: 13.92.

Found: C: 47.04; H, 3.67; N, 10.27; S: 7.75; F: 13.93.

Na content by atomic absorption spectrometry: 5.6% (Calculated: 5.62%)

TABLE 3 relative half-value d-value intensity 2θ (°) width [Å] [%] 9.9400.188 8.8912 57 10.440 0.212 8.4665 35 15.700 0.306 5.6398 40 16.9000.259 5.2419 100 18.300 0.259 4.8439 30 20.960 0.141 4.2348 37 21.1200.141 4.2031 35 21.720 0.282 4.0883 45 24.740 0.141 3.5957 25 26.4800.306 3.3632 27

Example 4

The magnesium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole

(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(1.11 g, 3.0 mmol) was dissolved in methanol (10 mL), and 25% aqueousammonia (0.34 mL, 4.5 mmol) and then magnesium sulfate heptahydrate (555mg, 2.25 mmol) were added thereto. After stirring at a room temperatureovernight, an insoluble matter was filtrated off, and the filtrate wasconcentrated under a reduced pressure. The residue was dissolved inmethanol (10 mL) again, and water (10 mL) was slowly added dropwisethereto with stirring. After stirring for about 4 hours, theprecipitated solid was filtrated, washed with water-methanol (4:1) anddried under a reduced pressure to obtain crude magnesium salt in theform of a colorless amorphous (747 mg). To the crude magnesium salt (720mg) was added ethanol-ether (ethanol:ether=5:95, 20 mL). Afterultrasonic treating the mixture and successively heating the mixture toabout 35° C., the salt was filtrated and washed with ether. The sameoperation was repeated. The resulting powder solid was dissolved inethanol (2 mL), and ether (40 mL) was gradually added dropwise theretowith stirring. After stirring overnight, the precipitated solid wasfiltrated and washed with ether. After drying the solid at 60° C. undera reduced pressure, the title compound (430 mg) was obtained as anamorphous.

Elemental Analysis

Calculated (as C₃₂H₂₆N₆O₄S₂F₆Mg.4.5H₂O):

C: 45.64; H 4.19; N, 9.98.

Found: C: 45.67; H, 4.19; N, 9.80.

Mg content by atomic absorption spectrometry: 2.9% (Calculated: 2.89%)

Water content result evaluated: 8.7%

Example 5

The magnesium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole

To(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(5.0 g, 0.014 mol) were added 8% magnesium ethoxide (6.5 g, 0.006 mol)and methanol (5 mL) to dissolve. The mixture was concentrated under areduced pressure, and to the residue was added tert-butyl methyl ether(100 mL) to crystallize. The precipitated solid was separated and washedwith tert-butyl methyl ether (10 mL). After drying at 40° C. under areduced pressure, the title compound (4.4 g) was obtained as anamorphous.

Elemental Analysis

Calculated (as C₃₂H₂₆N₆O₄S₂F₆Mg.1.5CH₃OH.2.5H₂O):

C: 47.11; H 4.37; N, 9.84; S: 7.51; F: 13.35.

Found: C: 47.21; H, 4.40; N, 9.79; S: 7.58;F: 13.21 Mg content by atomicabsorption spectrometry: 2.8%. (Calculated: 2.85%)

Example 6

The crystal of potassium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy) 2pyridinyl]methyl]sulfinyl]-1H-benzimidazole

To an ethanol solution (10 mL) of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy]-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(1.00 g) was added 10% potassium hydroxide aqueous solution (1.53 mL)under cooling with an ice. After concentrating the mixture under areduced pressure, the residue was dissolved by adding ethanol (10 mL),and concentrated under a reduced pressure. The residue was repeatedlydissolved by adding ethanol (10 mL) and the resultant mixture wasconcentrated under a reduced pressure. To the resulting foamy materialwas added diethyl ether (10 mL), and after ultrasonic treatment, themixture was allowed to stand and supernatant was removed off. Anotherdiethyl ether (10 mL) was added to the resultant precipitated residue,and after ultrasonic treatment, the resultant mixture was allowed tostand and supernatant was removed off. Diethyl ether (10 mL) was addedto the residue, and the resultant mixture was stirred for 20 minutes.Then, the precipitated solid was filtrated and washed with diethyl ether(10 mL). The resultant solid was dried at 60° C. under a reducedpressure to give 0.951 g of white powder.

The resulting white powder (0.43 g) was suspended in diethyl ether (15mL), and the suspension was heated with refluxing for 14 hours. Aftercooling the resultant mixture to a room temperature, diethyl ether wasremoved off, and toluene (20 mL) was added to the residue andsuccessively the mixture was heated with refluxing for 10 minutes. Aftercooling to a room temperature, toluene was removed off, isopropyl etherwas added to the residue and the mixture was heated with refluxing for25 minutes. After cooling to a room temperature, isopropyl ether wasremoved off and toluene (20 mL) was added to the residue andsuccessively the mixture was heated with refluxing for 35 minutes. Aftercooling to a room temperature, the precipitated solid was filtrated andwashed with diethyl ether. After drying at 80° C. under a reducedpressure, the title compound (0.218 g) was obtained. The data of X-raypowder diffraction is shown in Table 4, and the chart of X-ray powderdiffraction is shown in FIG. 4.

Elemental Analysis

Calculated (as C₁₆H₁₃N₃O₂SF₃K.0.75H₂O):

C: 45.65; H 3.47; N, 9.98.

Found: C: 45.83; H, 3.71; N, 9.97.

K content by atomic absorption spectrometry: 9.0% (Calculated: 9.29%)

¹H-NMR (DMSO-d₆): 2.23 (3H,$), 4.42 (1H, d, J=12.8 Hz), 4.82-4.95 (3H,m), 6.85-6.91 (2H, m), 7.06 (1H, d, J=5.4 Hz), 7.43-7.48 (2H, m), 8.35(1H, d, J=5.4 Hz)

TABLE 4 relative half-value d-value intensity 2θ (°) width [Å] [%] 5.4000.118 16.3519 100 10.820 0.165 8.1700 21 12.980 0.165 6.8148 18 15.3200.165 5.7788 32 17.980 0.165 4.9294 17 19.720 0.165 4.4982 36 20.8800.141 4.2509 26 21.760 0.188 4.0809 21 24.380 0.212 3.6480 19 26.4800.141 3.3632 24 29.520 0.118 3.0234 18

Experimental Example 1

The crystal of a sodium salt obtained in Example 1 (about 5 mg) wasserved into a colorless glass bottle, the bottle was hermetically sealedby a stopper, and stability of the crystal during storage at 60° C. for4 weeks was examined. 25 ml of a sample (concentration: about 0.2 mg/ml)was prepared by dissolving the sample after completion of storage in amobile phase. The sample solution along with a standard solutionprepared by using the initial lot (a frozen sample stored for the sameterm), was analyzed under the HPLC conditions shown below, and thecontent (residual percentage) was calculated from the peak areaobtained.

[HPLC Analytical Conditions]

Detection wavelength: UV 275 nm

Column: YMC Pro C18, 4.6φ 150 mm

Mobile phase: Fluid prepared by adding phosphoric acid towater/acetonitrile/triethylamine (63:37:1) to adjust pH 7

Flow rate: 1.0 mL/min

Column temperature: 40° C.

Sample injection volume: 10 μL

TABLE 5 storage content sample condition description [%] crystal of Ex.1 freeze-storage nearly white [100] crystal of Ex. 1 60° C. (airtight)nearly white  99.2 for 4 weeks

As apparent from Table 5, when the sample was stored at 60° C.(airtight) for 4 weeks, the crystal retained a content exceeding 99%.This finding demonstrates that the crystal of a sodium salt ofR(+)-lansoprazole is stable and suitable for use as a pharmaceuticaletc.

Manufacturing Example 1

Among the following ingredients, sodium salt of Example 1, magnesiumcarbonate, saccharose, corn starch and crystalline cellulose werethoroughly mixed together to obtain a dusting powder. Nonpareils wereput on a centrifugal fluidized coating granulatar (CF-360, manufacturedby Freund Inc.) and then the dusting powder was coated while spraying ahydroxypropyl cellulose solution (4%: W/V) to give spherical granules.The spherical granules were dried in vacuum at 40° C. for 16 hours andthen passed through round sieve to give 12 to 32-mesh granules.

[Formulation in 190 Mg of Granules]

nonpareil 75 mg sodium salt of Example 1 15 mg magnesium carbonate 15 mgsaccharose 29 mg corn starch 27 mg crystalline cellulose 27 mghydroxypropyl cellulose 2 mg water (0.05 ml) total 190 mg

Manufacturing Example 2

Enteric granules were produced by coating the granules obtained inManufacturing Example 1 with an enteric coating agent having a formationshown below by means of a fluidized bed granulator (manufactured byOkawara) under conditions such that the inlet air temperature was 50° C.and the granule temperature was 40° C. The no. 2 hard capsule was filledwith the enteric granules thus obtained in an amount of 240 mg percapsule using a capsule filling machine (manufactured by Parke-Davis).

[Formulation of Enteric Coating Agent]

Eudragit L-30D 104.7 mg (solids 31.4 mg) Talc 9.6 mg Polyethylene glycol6000 3.2 mg Tween 80 1.6 mg Titanium oxide 4.2 mg Water (220 μl)

[Formulation of Enteric Granules]

Granules of Manufacturing Example 1 190 mg Enteric coat  50 mg Total 240mg

[Formulation of Capsule]

Enteric granules 240 mg No. 2 hard capsule  65 mg Total 305 mg

The invention claimed is:
 1. A crystal of sodium salt of(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazoleMonohydrate, wherein the X-ray diffraction spectrum have the followingdiffraction peaks: (iii) 8.89, 8.47, 5.64, 5.24, 4.84, 4.23, 4.20, 4.09,3.60, and 3.36 Angstrom.